The specific aims of our research have been derived from the findings that we have made during the first two and one-half years of NIDA support to study"Cardiorespiratory Effects of Cocaine" Our first aim will be to continue in our pursuit of characterizing the effects of cocaine on the sympathetic nervous system. Hypotheses that will be tested are that cocaine administration: (1) in i.v. doses of 0.0625 to 0.25 mg/kg will augment the effects of cardiac sympathetic nerve stimulation on the heart; however, doses above 2 mg/kg and above will not exhibit an augmenting effect; (2) will result in inhibition of central sympathetic outflow to the heart; and the site of this effect is the ventrolateral medulla (subretrofacial nucleus); (3) will result in inhibition of ganglionic transmission due to inhibition of norepinephrine uptake in the ganglia; (4) will result in selective stimulation of the adrenal medulla, leading to an increase in plasma epinephrine levels; (5) will result in sympathetically- mediated contraction of the isolated coronary artery, as well as sympathetically-mediated release of endothelial relaxing factor; (6) will result in tachyphylaxis to the sympathomimetic effects of the drug and the tachyphylaxis will e reversible after blockade of presynaptic alpha2- adrenoceptors; and (7) in repeated doses over a period of several hours ("run") will result in down regulation of adrenoceptors. Our second aim will be to continue in our pursuit of characterizing the direct effects of cocaine on cardiac and neural tissues. Hypotheses that will be tested are that: (1) cocaine's direct effects on the heart resemble more closely the drug flecainide than the drug lidocaine; (2) cocaine acts directly on cardiac tissue to counteract Ca2+ entry into A-V nodal cells; and (3) cocaine's direct negative inotropic effect is not counteracted by its sympathomimetic effect. Our third aim is to determine whether ethanol and nicotine as well as interference with the activity of plasma cholinesterase will predispose subjects to cocaine-cardiotoxicity. Our fourth aim will be to use information obtained from pursuing Aims 1-3 as a basis for developing drugs that would prevent and/or counteract cardiovascular disorders associated with cocaine abuse. We will also determine whether any deleterious actions occur on the cardiovascular system when drugs that are proposed to interfere with drug taking behavior (e.g., tricyclic experimental animals using standard techniques that are for the most part on-going in our laboratories. Our findings will provide: (1) new information on the pharmacology of cocaine, and information on nay deleterious effects that might occur when drugs which might interfere with drug taking behavior are combined with cocaine. (2) a rationale basis for selecting drugs to counter neurocardiovascular effects of the drug.